Longitudinal associations of light-intensity physical activity with quality of life, functioning and fatigue after colorectal cancer.

PURPOSE: Evidence from cross-sectional studies suggests that higher levels of light-intensity physical activity (LPA) are associated with better health-related quality of life (HRQoL) in colorectal cancer (CRC) survivors. However, these associations have not been investigated in longitudinal studies that provide the opportunity to analyse how within-individual changes in LPA affect HRQoL. We investigated longitudinal associations of LPA with HRQoL outcomes in CRC survivors, from 6 weeks to 2 years post-treatment. METHODS: Data were used of a prospective cohort study among 325 stage I-III CRC survivors (67% men, mean age: 67 years), recruited between 2012 and 2016. Validated questionnaires were used to assess hours/week of LPA (SQUASH) and HRQoL outcomes (EORTC QLQ-C30, Checklist Individual Strength) at 6 weeks, and 6, 12 and 24 months post-treatment. We applied linear mixed regression to analyse longitudinal confounder-adjusted associations of LPA with HRQoL. RESULTS: We observed statistically significant longitudinal associations between more LPA and better global quality of life and physical, role and social functioning, and less fatigue over time. Intra-individual analysis showed that within-person increases in LPA (per 8 h/week) were related to improved HRQoL, including better global quality of life (ß = 1.67, 95% CI 0.71; 2.63; total range scale: 0-100) and less fatigue (ß = - 1.22, 95% CI - 2.37; - 0.07; scale: 20-140). Stratified analyses indicated stronger associations among participants below the median of moderate-to-vigorous physical activity (MVPA) at diagnosis. CONCLUSION: Higher levels of LPA were longitudinally associated with better HRQoL and less fatigue in CRC survivors up to two years post-treatment. Further prospective studies using accelerometer data are necessary to inform development of interventions targeting LPA.

Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: real-life data from The Netherlands.

BACKGROUND: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. METHODS: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). RESULTS: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8-2.3) and 5.4 months (95% CI, 4.0-6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0-1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. CONCLUSIONS: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. FUNDING: Johannes J.M. Kwakman received an unrestricted research grant from Servier.

Short-Course Radiotherapy Followed by Neoadjuvant Bevacizumab, Capecitabine, and Oxaliplatin and Subsequent Radical Treatment in Primary Stage IV Rectal Cancer: Long-Term Results of a Phase II Study.

BACKGROUND: In a Dutch phase II trial conducted between 2006 and 2010, short-course radiotherapy followed by systemic therapy with capecitabine, oxaliplatin, and bevacizumab as neoadjuvant treatment and subsequent radical surgical treatment of primary tumor and metastatic sites was evaluated. In this study, we report the long-term results after a minimum follow-up of 6 years. METHODS: Patients with histologically confirmed rectal adenocarcinoma with potentially resectable or ablatable metastases in liver or lungs were eligible. Follow-up data were collected for all patients enrolled in the trial. Overall and recurrence-free survival were calculated using the Kaplan-Meier method. RESULTS: Follow-up data were available for all 50 patients. After a median follow-up time of 8.1 years (range 6.0-9.8), 16 patients (32.0%) were still alive and 14 (28%) were disease-free. The median overall survival was 3.8 years (range 0.5-9.4). From the 36 patients who received radical treatment, two (5.6%) had a local recurrence and 29 (80.6%) had a distant recurrence. CONCLUSIONS: Long-term survival can be achieved in patients with primary metastatic rectal cancer after neoadjuvant radio- and chemotherapy. Despite a high number of recurrences, 32% of patients were alive after a median follow-up time of 8.1 years.

Effects of five Ayurvedic herbs on locomotor behaviour in a Drosophila melanogaster Parkinson's disease model.

Current conventional treatments for Parkinson's disease (PD) are aimed at symptom management, as there is currently no known cure or treatment that can slow down its progression. Ayurveda, the ancient medical system of India, uses a combination of herbs to combat the disease. Herbs commonly used for this purpose are Zandopa (containing Mucuna pruriens), Withania somnifera, Centella asiatica, Sida cordifolia and Bacopa monnieri. In this study, these herbs were tested for their potential ability to improve climbing ability of a fruit fly (Drosophila melanogaster) PD model based on loss of function of phosphatase and tensin-induced putative kinase 1 (PINK1). Fruit flies were cultured on food containing individual herbs or herbal formulations, a combination of all five herbs, levodopa (positive control) or no treatment (negative control). Tests were performed in both PINK1 mutant flies and healthy wild-type (WT) flies. A significant improvement in climbing ability was observed in flies treated with B. monnieri compared with untreated PINK1 mutant flies. However, a significant decrease in climbing ability was observed in WT flies for the same herb. Centella asiatica also significantly decreased climbing ability in WT flies. No significant effects were observed with any of the other herbs in either PINK1 or WT flies compared with untreated flies.

Modern multidisciplinary treatment of rectal cancer based on staging with magnetic resonance imaging leads to excellent local control, but distant control remains a challenge.

AIM: The purpose of this multicenter cohort study was to evaluate whether a differentiated treatment of primary rectal cancer based on magnetic resonance imaging (MRI) can reduce the number of incomplete resections and local recurrences and improve recurrence-free and overall survival. METHODS: From February 2003 until January 2008, 296 patients with rectal cancer underwent preoperative MRI using a lymph node specific contrast agent to predict circumferential resection margin (CRM), T- and N-stage. Based on expert reading of the MRI, patients were stratified in: (a) low risk for local recurrence (CRM>2mm and N0 status), (b) intermediate risk and (c) high risk (close/involved CRM, N2 status or distal tumours). Mainly based on this MRI risk assessment patients were treated with (a) surgery only (TME or local excision), (b) preoperative 5 × 5 Gy+TME and (c) a long course of chemoradiation therapy followed by surgery after a 6-8 week interval. RESULTS: Overall 228 patients underwent treatment with curative intent: 49 with surgery only, 86 with 5 × 5 Gy and surgery and 93 with chemoradiation and surgery. The number of complete resections (margin>1mm) was 218 (95.6%). At a median follow-up of 41 months the three-year local recurrence rate, disease-free survival rate and overall survival rate is 2.2%, 80% and 84.5%, respectively. CONCLUSION: With a differentiated multimodality treatment based on dedicated preoperative MR imaging, local recurrence is no longer the main problem in rectal cancer treatment. The new challenges are early diagnosis and treatment, reducing morbidity of treatment and preferably prevention of metastatic disease.

HLA-matched allo-SCT after reduced intensity conditioning with fludarabine/CY in patients with metastatic breast cancer.

Fifteen patients with chemosensitive metastatic breast cancer (MBC) underwent reduced intensity (RIST) allo-SCT between 1999 and 2006. The purpose of this single-center study was to evaluate the feasibility, safety and efficacy of this therapeutic approach. The pretransplant conditioning regimen consisted of fludarabine (25 mg/m(2) at days -5 to -1) and CY (60 mg/kg at days -2, -1). Stem cells were from HLA-matched sibling donors. The treatment-related mortality was 2/15 (13%). Median PFS and OS were 144 days (43-509 days) and 303 days (122-1376 days), respectively. The 1-year PFS was 20%, and the 1-year and 2-year OS was 40 and 20%, respectively. No objective tumor responses were observed, but the relatively long PFS does suggest a graft-vs-tumor effect. Although RIST using this CY/fludarabine regimen is feasible, the efficacy in this set of patients was limited. Future clinical trials should be performed to improve the knowledge of mechanisms of antitumor effects in breast cancer.

[Angiogenesis inhibitors for the systemic treatment of metastatic renal cell carcinoma: sunitinib, sorafenib, bevacizumab and temsirolimus]. / Angiogeneseremmers voor de systemische behandeling van gemetastaseerd niercelcarcinoom: sunitinib, sorafenib, bevacizumab en temsirolimus.

Treatment of patients with metastatic renal cell carcinoma is evolving rapidly due to the advent of novel targeted therapies. Improved knowledge of the underlying pathogenesis has led to the development of drugs that modulate the dominant signal transduction pathways for this disease, which results in inhibition of angiogenesis. Recent evidence indicates that the receptor tyrosine kinase inhibitor sunitinib prolongs progression-free survival compared with interferon-alpha, especially in patients with intermediate risk. Immunotherapy with interferon-alpha or high-dose interleukin-2 should still be considered for low-risk patients, particularly those with clear-cell tumours and metastases of the lung only. In patients who fail treatment with interferon-alpha, sorafenib has been shown to improve progression-free survival. High-risk patients may benefit from treatment with temsirolimus, which inhibits mammalian target of rapamycin (mTOR) kinase activity and has shown to improve overall survival. These angiogenesis inhibitors did not receive mention in the recently published guideline 'Renal cell carcinoma'.

Primary monophasic mediastinal, cardiac and pericardial synovial sarcoma: a young man in distress.

A 19-year-old male was admitted because of exertional dyspnoea. The imaging studies revealed epicardial, pericardial and mediastinal masses. The tumours could not be resected through a minor thoracotomy, only biopsies could be taken. Analyses led to the final diagnosis of a monophasic synovial sarcoma. The patient preferred a conservative and palliative approach. Three months later he died at home. Autopsy demonstrated dramatic extension of the tumour masses. We conclude this report with a discussion on primary cardiac tumours. (Neth Heart J 2007;15:226-8.).

High-dose 5-fluorouracil plus low dose methotrexate plus or minus low-dose PALA in advanced colorectal cancer: a randomised phase II-III trial of the EORTC Gastrointestinal Group.

The aim of this study was to investigate whether N-(phosphonacetyl)-L-aspartic acid (PALA) can enhance the activity of low-dose methotrexate (LD-MTX) modulated infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. 198 patients were randomised either to (i) 5-FU 60 mg/kg as a continuous infusion over 48 h, to be given weekly four times and thereafter every 2 weeks, with methotrexate 40 mg/m(2) administered just before 5-FU (control regimen) or to (ii) PALA 250 mg/m(2) as a 15 min infusion administered 24 h before 5-FU and methotrexate which was given as described in the control regimen. The response rate was 13% in the patients randomised to the control arm and 7% in the patients randomised to the experimental arm. If stabilisation of the disease was also considered as a positive response, these figures become 54 and 46%, respectively. All these differences did not reach statistical significance. The median durations of progression-free survival (PFS) in the two treatment groups were not significantly different. The median duration of survival was 13.1 months in the control arm and 11.9 months in the experimental arm (P=0.31). No benefit was obtained by adding PALA to LD-MTX+infusional FU. Taking into account data from US trials, the modulating effect of PALA, although 'promising' in phase II, could not be substantiated in randomised studies.

The unknown biology of the unknown primary tumour: a literature review.

The unknown primary tumour (UPT) is an intriguing clinical phenomenon found in approximately 5% of all newly diagnosed patients with cancer. It is unclear whether UPT forms a distinct biological entity with specific genetic and phenotypic characteristics, or whether it is merely a clinical presentation of metastases in patients in whom the primary tumour cannot be detected and does not result in any visible clinical signs. Understanding the basic biology of UPT may shed light on this issue and, moreover, may have a direct impact on clinical care. A review of the literature revealed only a limited number of publications describing the genetic and phenotypic features of UPT, most of which focus only on the potential of these markers to predict prognosis. The question as to whether the biology of UPT is different from tumours of known primaries therefore remains unanswered. Further insight into the molecular mechanisms underlying the oncogenesis of UPT, e.g. by applying newly available DNA and gene profiling microarray techniques, will be necessary to understand its specific biology and to develop more effective treatments.

Clinical relevance of apoptotic markers in breast cancer not yet clear.

Currently, the mainly used characteristics to predict outcome or treatment response in patients with breast cancer are tumor size, N-status, histological grade and receptor status (ER/PgR). However, these conventional clinico-pathological characteristics are of limited value. More accurate determinators are needed to select patients who are most likely to benefit from treatment in terms of prognosis as well as treatment response. Proliferation and apoptosis are assumed to play a key role in tumor progression as well as response to treatment. Currently, an increasing number of molecular factors controlling apoptosis as well as proliferation is known. The clinical relevance of apoptotic tumor markers in the treatment strategy of patients with breast cancer is the subject of this review. In addition, potential future developments are discussed.

Modulation of the cytochrome P450-mediated metabolism of ifosfamide by ketoconazole and rifampin.

BACKGROUND: The autoinducible metabolic transformation of the anticancer agent ifosfamide involves activation through 4-hydroxyifosfamide to the ultimate cytotoxic ifosforamide mustard and deactivation to 2- and 3-dechloroethylifosfamide with concomitant release of the neurotoxic chloroacetaldehyde. Activation is mediated by cytochrome P450 (CYP) 3A4 and deactivation by CYP3A4 and CYP2B6. The aim of this study was to investigate modulation of the CYP-mediated metabolism of ifosfamide with ketoconazole, a potent inhibitor of CYP3A4, and rifampin (INN, rifampicin), an inducer of CYP3A4/CYP2B6. METHODS: In a double-randomized, 2-way crossover study a total of 16 patients received ifosfamide 3 g/m(2) per 24 hours intravenously, either alone or in combination with 200 mg ketoconazole twice daily (1 day before treatment and 3 days of concomitant administration) or 300 mg rifampin twice daily (3 days before treatment and 3 days of concomitant administration). Plasma pharmacokinetics and urinary excretion of ifosfamide, 2- and 3-dechloroethylifosfamide, and 4-hydroxyifosfamide were assessed in both courses. Data analysis was performed with a population pharmacokinetic model with a description of autoinduction of ifosfamide. RESULTS: Rifampin increased the clearance of ifosfamide at the start of therapy at 102%. The fraction of ifosfamide metabolized to the dechloroethylated metabolites was increased, whereas exposure to the metabolites was decreased as a result of increased elimination. The fraction metabolized and the exposure to 4-hydroxyifosfamide were not significantly influenced. Ketoconazole did not affect the fraction metabolized or the exposure to the dechloroethylated metabolites, whereas both parameters were reduced with 4-hydroxyifosfamide. CONCLUSIONS: Coadministration of ifosfamide with ketoconazole or rifampin did not produce changes in the pharmacokinetics of the parent or metabolites that may result in an increased benefit of ifosfamide therapy.

Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites.

This review discusses several issues in the clinical pharmacology of the antitumour agent ifosfamide and its metabolites. Ifosfamide is effective in a large number of malignant diseases. Its use, however, can be accompanied by haematological toxicity, neurotoxicity and nephrotoxicity. Since its development in the middle of the 1960s, most of the extensive metabolism of ifosfamide has been elucidated. Identification of specific isoenzymes responsible for ifosfamide metabolism may lead to an improved efficacy/toxicity ratio by modulation of the metabolic pathways. Whether ifosfamide is specifically transported by erythrocytes and which activated ifosfamide metabolites play a key role in this transport is currently being debated. In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely understood. Assessment of the pharmacokinetics of ifosfamide and metabolites has long been impaired by the lack of reliable bioanalytical assays. The recent development of improved bioanalytical assays has changed this dramatically, allowing extensive pharmacokinetic assessment, identifying key issues such as population differences in pharmacokinetic parameters, differences in elimination dependent upon route and schedule of administration, implications of the chirality of the drug and interpatient pharmacokinetic variability. The mechanisms of action of cytotoxicity, neurotoxicity, urotoxicity and nephrotoxicity have been pivotal issues in the assessment of the pharmacodynamics of ifosfamide. Correlations between the new insights into ifosfamide metabolism, pharmacokinetics and pharmacodynamics will rationalise the further development of therapeutic drug monitoring and dose individualisation of ifosfamide treatment.

Anti-apoptotic phenotype is associated with decreased locoregional recurrence rate in breast cancer.

PURPOSE: Tumor stage and nodal status are the most important factors predicting locoregional recurrence in breast cancer. We wanted to investigate the prognostic value of some newer molecular genetic markers for the occurrence of a locoregional recurrence, in order to improve the selection of patients for locoregional adjuvant therapy. METHODS: Bcl-2, p53, MIB-1, pS2 and CD44v6 were determined immunohistochemically on formalin-fixed and paraffin embedded tumour tissues of 163 patients treated by modified radical mastectomy between 1982 and 1987. Postoperative irradiation was given to 35 patients to the intermammary chain only and to only 13 (8%) patients to the chest wall with or without the regional lymph nodes. Node-positive patients were treated with CAF adjuvant chemotherapy and were randomized for whether or no additional Medroxyprogesteroneacetate (MPA). A multivariate analysis was performed on a number of potential prognostic factors. The risk for locoregional recurrence was estimated using the competing risk approach. RESULTS: After a median period of 7.5 years 28 patients developed a locoregional recurrence. The cumulative incidence of loco-regional recurrence at 10 years was 17%. Bcl-2 and p53 were found to be independent factors predicting locoregional recurrence, whereas a trend was found for MIB-1. Increased Bcl-2 as well as p53 expression were associated with a decreased risk, whereas the increased presence of MIB-1 was associated with an increased risk. CONCLUSION: Results indicate that molecular markers of apoptosis as well as proliferation provide additional information for the risk of locoregional recurrence after modified radical mastectomy. If confirmed, these markers may play a role in the selection of appropriate locoregional adjuvant treatment after primary surgery.

Immunochemotherapy with interleukin-2, interferon-alpha and 5-fluorouracil for progressive metastatic renal cell carcinoma: a multicenter phase II study. Dutch Immunotherapy Working Party.

In patients with metastatic renal cell carcinoma response rates of 7-26% have been achieved with immunotherapy. A high response rate of 48% in 35 patients has been reported for treatment with the combination of interferon-alpha (IFN-alpha), interleukin-2 (IL-2) and 5-fluorouracil (5-FU) (Atzpodien et al (1993a) Eur J Cancer29A: S6-8). We conducted a multicentre phase II study to confirm these results. Metastatic renal cell carcinoma patients were treated as outpatients with an 8-week treatment cycle. Recombinant human IL-2 20 MU m(-2) was administered subcutaneously (s.c.) three times a week (t.i.w) in weeks 1 and 4 and 5 MU m(-2) t.i.w. in weeks 2 and 3. Recombinant human IFN-alpha 2a 6 MU m(-2) was administered s.c. once in weeks 1 and 4 and t.i.w. in weeks 2 and 3, and 9 MU m(-2) t.i.w. in weeks 5-8. 5-FU (750 mg m(-2)) was given as a bolus injection intravenous once a week in weeks 5-8. The treatment cycle was repeated once in case of response or minor response. Fifty-two patients entered the study. All had undergone a nephrectomy and had progressive metastatic disease. The median WHO-performance status was 1, the median number of metastatic sites was 2 (range 1-5) and the median time between the diagnosis of the primary tumour and the start of treatment was 12.9 months (range 1-153). Among the 51 patients, including four patients with early progressive disease, who were evaluable for response, the response rate was 11.8% (95% confidence interval (CI) 2.9-20.7%), with no complete responses. Median duration of response was 8.3 (range 3.8-22.4+) months. Median survival was 16.5 (range 1.8-30.5+) months. Grade 3/4 toxicity (WHO) occurred in 29/52 (55.8%) of the patients in cycle 1 and in 6/16 (37.5%) of the patients in cycle 2. It consisted mainly of anorexia, fatigue, nausea, fever and leucocytopenia. We cannot confirm the high response rate in patients with metastatic renal cell carcinoma treated with the combination of IFN-alpha, IL-2 and 5-FU, as described by Atzpodien et al.

Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections.

It has been suggested that a better outcome of neutropenia-associated invasive fungal infections can be achieved when high doses of lipid formulations of amphotericin B are used. We now report a randomized multicentre study comparing liposomal amphotericin B (AmBisome, 5 mg/kg/d) to amphotericin B deoxycholate (AmB, 1 mg/kg/d) in the treatment of these infections. Of 106 possible patients, 66 were enrolled and analysed for efficacy: nine had documented fungaemia, 17 had other invasive mould infections and 40 had suspected pulmonary aspergillosis. After completion of the course medication, in the AmBisome group (n = 32) 14 patients had achieved complete response, seven a partial response and 11 were failures as compared to 6, 13 and 15 patients (n = 34) treated with AmB (P=0.09); P=0.03 for complete responders. A favourable trend for AmBisome was found at day 14, in patients with documented infections and in patients with pulmonary aspergillosis (P=0.05 and P=0.096 respectively). Mortality rates were lower in patients treated with AmBisome (adjusted for malignancy status, P=0.03). More patients on AmB had a >100% increase of their baseline serum creatinine (P<0.001). The results indicate that, in neutropenic patients with documented or suspected invasive fungal infections AmBisome 5 mg/kg/d was superior to AmB 1 mg/kg/d with respect to efficacy and safety.

MIB-1 labelling index is an independent prognostic marker in primary breast cancer.

The proliferative activity of a tumour is considered to be an important prognostic factor in primary breast cancer. We have investigated the prognostic value of the MIB-1 labelling index in 341 patients with primary breast cancer and compared the results with the S-phase fraction in 220 patients of the same cohort. All patients were treated in one hospital and had a median follow-up of 128 months. No correlation between MIB-1 labelling and S-phase fraction could be demonstrated. MIB-1 had prognostic value for disease-free survival in the whole group of patients (P < 0.001) and in the node-negative subgroup (P < 0.001). In multivariate analysis, MIB-1 was an independent prognostic factor (P = 0.004) besides axillary lymph node status (P = 0.001). In univariate analysis high S-phase fraction was associated with decreased overall survival (P = 0.04); however, not in multivariate analysis. Moreover, S-phase fraction had a borderline prognostic significance for post-relapse survival in multivariate analysis (P= 0.08). Thus, in conclusion, the growth fraction of a tumour as determined by the MIB-1 labelling index is an important prognostic factor in patients with primary breast cancer.

pS2 is an independent prognostic factor for post-relapse survival in primary breast cancer.

BACKGROUND: The pS2 protein is involved in the maintenance of the integrity of the gastrointestinal tract. In breast cancer pS2 can be demonstrated in at least half of the tumors and probably reflects the functional status of ER. Several features make it likely that pS2 is involved in growth regulation. PATIENTS AND METHODS: We have investigated the value of immunohistochemical pS2 determination as a prognostic factor in 339 breast cancer patients with long follow-up from one hospital. RESULTS: A prognostic role for pS2 could not be demonstrated considering disease-free and overall survival, although in pS2-negative tumors a trend for less locoregional relapse was found. However, in multivariate analysis pS2 showed independent prognostic value for post-relapse survival. CONCLUSIONS: PS2 is an independent prognostic factor for post-relapse survival, most likely because it is a predictive factor for response to systemic therapy.

High-dose chemotherapy with autologous bone marrow support as consolidation after standard-dose adjuvant therapy in primary breast cancer patients with seven or more involved axillary lymph nodes.

Despite adjuvant chemotherapy the prognosis of patients with breast cancer and a high number of involved axillary lymph nodes is very poor. The aim of the present study was to evaluate the efficacy of high-dose chemotherapy with autologous bone marrow support in patients with seven or more involved axillary lymph nodes. Nineteen patients underwent four courses of standard adjuvant chemotherapy, followed by high-dose busulphan/cyclophosphamide chemotherapy with autologous bone marrow support. The median age was 41.4 years and the median number of involved lymph nodes 11. Mucositis WHO grade > or = 3 was observed in 15 patients and 18 patients suffered febrile neutropenia. Transplant-related mortality was encountered in two patients, due to hepatic veno-occlusive disease and sepsis complicated by multi-organ failure, respectively. After a median follow-up period of 1490 days (range 582-2024 days) from diagnosis, nine patients have relapsed and the overall event-free survival (EFS) is 42% (95% CI 19-65%). The median EFS is 487 days. High-dose treatment with BuCy2 in high-risk breast cancer patients is a toxic regimen and does not seem to improve disease-free survival.